A central question in neuroimmunology concerns the mechanisms whereby information about peripheral immune activation is communicated to the brain. The cytokine cascade at the level of the blood-brain barrier (BBB) provides on likely pathway. Interleukin-6(IL-6) is reliably released in large quantities into the cerebrospinal fluid (CSF) following peripheral administration of IL-1. The 3 studies proposed for this fellowship are designed to further characterize this IL-6 response:1)to identify one possible cellular source of CSF IL-6,2)to analyze IL-6 bioactivity in blood and intrathecal compartments, and 3)to define a potential function for IL-6 in the CSF. Monkey endothelial cell cultures will be established to examine whether cells of the BBB can produce IL-6 upon stimulation with IL-1. To further localize the source of IL-6, an in vivo study will determine if an IL-6 concentration gradient exists within the intrathecal compartment. Soluble IL-6 receptor (sIL-6R), an endogenous agonist found in the blood can potentiate IL-6 effects, but it is absent from the CSF. Therefore, bioactivity of blood and CSF samples will be assessed during the IL-6 dependent cell lines, B9 and 7TD1. Lastly, IL-6 has effects on many neural and lymphoid cells, possibly including leukocytes in CSF. The influence of CSF (both with and without IL-6) on lymphocyte proliferation will be investigated. Characterization of IL-6 within CSF has important implications for understanding cytokine communication between the periphery and the CNS. Furthermore, these findings are relevant to diseases with neuroimmune sequelae, involving high cytokine levels or leukocyte infiltration into the CNS.